Leukocytes and Coronary Artery Disease Experimental and Clinical Studies

Abstract: Tissue factor (TF) is the initiator of the coagulation cascade. Monocytes do not normally express TF, but can be induced to do so by certain stimuli. Aberrant TF expression is important in the thrombotic complications of bacterial sepsis, certain malignancies and coronary artery disease (CAD). In this thesis, regulation of monocyte TF by cytokines and by interactions with other vascular cells were studied, as well as the activation of blood cells, inflammation and coagulation in CAD patients and the association of the pro-inflammatory cytokine interleukin (IL)-6 with prognosis in unstable CAD. In a whole blood experimental system, the anti-inflammatory cytokine IL-10 was shown to suppress lipopolysaccharide-induced TF expression in monocytes, whereas IL-4 and IL-13 did not, contrary to previous in vitro findings. Activated platelets also induced monocyte TF in whole blood in a P-selectin-dependent manner, causing a rapid surface exposure of TF independent of mRNA formation. The differentiated monocytic cell line U-937 displayed different kinetics of platelet-stimulated TF induction.In co-culture with cytokine-activated human coronary artery endothelial cells, U-937 cells expressed TF, and also IL-6. The endothelial cells up-regulated their production of IL-10. Simvastatin, enalapril and dalteparin, all commonly used drugs in CAD treatment, suppressed TF induction but did not alter cytokine expression in co-cultures.In unstable CAD, there was an activation of both coagulation and inflammation compared to stable CAD that coincided with an increased activation of platelets and leukocytes. Women had different patterns of cellular activation than men, indicating differences in pathogenetic mechanisms.Plasma levels of IL-6 above 5 ng/L proved to be a strong, independent marker for increased risk of death in a 6-12 month perspective in patients with unstable CAD. This risk was significantly reduced by an early invasive strategy.